Antiandrogenic agents are useful in the treatment of clinical conditions that are either androgen-responsive or associated with androgen excess, such as prostate carcinoma, benign prostatic hyperplasia (BPH), acne, seborrhea, alopecia, hirsutism, polycystic ovarian disease, and male pattern baldness. Antiandrogen therapy can be directed toward any of the regulatory steps in androgen production or action. The control of androgen production in the testis is directly mediated by hypothalamic-pituitary peptide hormones. Neurons of the hypothalamus secrete gonadotropin-releasing hormone (LHRH), a decapeptide that subsequently interacts with high-affinity cell surface receptor sites on the plasma membrane of pituitary cells. LHRH stimulates the release of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by a calcium-dependent mechanism.
LH secretion is controlled by the action of androgens and estrogens on the hypothalamus and pituitary. The control of LH in men occurs primarily by negative feedback since testicular steroids inhibit LH secretion. Both testosterone and estradiol can inhibit LH secretion. Although testosterone can be converted to estradiol in the brain and pituitary, the two hormones probably act independently. Testosterone acts on the central nervous system (CNS) to slow the hypothalamic pulse-generator and consequently decreases the frequency of LH pulsatile secretion. In addition, testosterone appears to have negative feedback on LH secretion in the pituitary.
LH reaches the testis via the peripheral circulation, where it interacts with specific high-affinity cell surface receptors on the plasma membranes of the Leydig cells. The binding of LH to its receptor stimulates biosynthesis of testosterone.
Although testosterone is the major secretory product, dihydrotestosterone (DHT), androsterone, androstenedione, progesterone, and 17-hydroxyprogesterone are also secreted by the testis.
In peripheral tissues, testosterone may act directly (e.g., in the CNS, skeletal muscle, and seminiferous epithelium), or serve as a circulating prohormone for the formation of DHT (e.g., prostate) and estrogen. In the prostate, testosterone diffuses into the cell, where it is reduced by 5-alpha reductase to DHT. Ninety percent of total prostatic androgen is in the form of DHT, principally derived from testicular androgens. The remaining 10% of the prostatic androgens are produced in the adrenal glands. Inside the cells of the prostate, both testosterone and DHT bind to the same high-affinity androgen-receptor protein. The hormone-receptor complex then binds to specific DNA binding sites in the nucleus of prostatic cells. This results in increased transcription of androgen-dependent genes and ultimately stimulation of protein synthesis. Conversely, androgen withdrawal from androgen-sensitive tissues results in a decrease in protein synthesis, tissue involution, and in some cases, cell death.
As noted above, a number of physiological problems are associated with androgen production. The most pressing of these at the present time is prostatic cancer, which is a leading cause of cancer in men, with on the order of 100,000 cases diagnosed and 26,000 deaths annually. The androgen dependence of some prostate cancers has been well-established and the primary therapy for metastatic prostate cancer involves androgen suppression. Androgen suppression can be achieved by: removal of the testis, the primary source of androgens, by orchiectomy; inhibition of testicular steroidogenesis at the pituitary level by either luteinizing hormone-releasing hormone analogs or estrogens; inhibition of testicular steroidogenesis at the testicular level using enzyme inhibitors; or inhibition of androgen action by androgen receptor antagonists.
Another important therapeutic area related to androgen production and action is the treatment of benign prostatic hyperplasea, a major problem in the aging human male (and a precursor to prostate cancer in about half of the cases diagnosed), with approximately 400,000 prostatectomies performed annually in the U.S. alone. Although surgery presently represents the most accepted treatment for BPH, several pharmacological approaches have been tested as well. However, no drug therapy has yet proven satisfactory.
Known antiandrogenic agents work by several mechanisms. There are those drugs which inhibit pituitary LH secretion and decrease testosterone and DHT production; these are termed "LHRH agonists," and include, for example, nafarelin, leuprolide, goserelin and buserelin. There are additional drugs which, similarly, inhibit pituitary LH secretion and decrease testosterone and DHT production, but also inhibit androgen receptors; these are drugs such as cyproterone acetate, zanoterone ("WIN.RTM.49,596," available from Sterling Winthrop) and the progestins, such as megestrol acetate, hydroxy-progesterone caproate and medrogestone, which exert their antiandrogenic effect through a negative feedback process. Other antiandrogenic drugs include the nonsteroidal agents hydroxyflutamide, Casodex.RTM., and nilutamide which are androgen receptor inhibitors, and 5-alpha-reductase inhibitors (e.g., finasteride), which decreases DHT selectivity. Structures of the representative antiandrogenic agents cyproterone acetate, Casodex.RTM., hydroxyflutamide (a flutamide metabolite) and WIN.RTM.49,596 are as follows: ##STR2##
The currently available antiandrogenic agents, however, are associated with a wide range of problems. For example, known antiandrogens give rise to a number of side effects, including impotence, loss of libido, gynecomastia, heat intolerance, and hot flashes, among others. Some drugs have even been associated with fatal hepatotoxicity (see, e.g., D. K. Wysowski et al., Ann. Int. Med. 118(11):860-864 (1993)). Additionally, the known drugs tend to have a very short half-life, necessitating more frequent and/or higher dosages.
The present invention is addressed to the aforementioned need in the art, and is premised on the discovery that certain novel 17-substituted steroids are useful as antiandrogenic agents, at relatively low doses, without causing the problems associated with the antiandrogenic compounds of the prior art. The novel compounds are thus useful for treating clinical conditions that are androgen-responsive and/or associated with androgen production, without giving rise to unwanted side effects as described above. The compounds are thus useful in the treatment of prostate carcinoma, benign prostatic hyperplasia, acne, seborrhea, alopecia, hirsutism, polycystic ovarian disease, and male pattern baldness. The compounds are additionally useful as male contraceptive agents. While not wishing to be bound by theory, the inventors herein postulate that the majority of these new agents appear to act as competitive androgen receptor antagonists by inhibiting prostate growth stimulated by exogenous testosterone, and are essentially devoid of progestational as well as agonist androgenic activity.